Stimulation of primary sensory neurons produces local vasodilation, plasma extravasation, and pain and is due largely to release of the neuropeptides substance P and calcitonin gene-related peptide (CGRP). Pathological activation of sensory neurons and the inflammatory sequelae are known as neurogenic inflammation and appear to be important in many organs systems including the pancreas. Factors that stimulate primary sensory neurons include hydrogen ions, heat, leukotrienes, arachidonic acid metabolites, bradykinin, and proteases such as trypsin, all of which may participate in the generation of acute pancreatitis. The current proposal examines the cellular and molecular mechanisms involved in sensory nerve activation within the pancreas and the contribution of neurogenic inflammation to the pathogenesis of pancreatitis. Primary sensory neurons are capsaicin-sensitive and express the capsaicin receptor [known as transient receptor potential vanilloid 1 (TRPV1)]. The PI has demonstrated that TRPV1 is activated in several models of pancreatitis including caerulein-induced pancreatitis and has extensive pharmacological data indicating that TRPV1 inhibition reduces the severity of pancreatitis. TRPV1 is activated by heat and protons, but it is unlikely that either high body temperature or acid directly activate TRPV1 in vivo. We have demonstrated that close arterial injection of leukotriene B4 (LTB4) into the pancreas causes pancreatic inflammation similar to caerulein and that this effect is blocked by an TRPV1 antagonist. Importantly, ethanol has been shown to lower the activation threshold of TRPV1 and we propose that ethanol may contribute to pancreatitis by activating primary sensory neurons. The current application is designed to test the hypothesis that primary sensory innervation is a necessary component of pancreatitis. The goal of this project is to define the events resulting from pancreatic injury that lead to sensory nerve activation and the initiation of pancreatitis. Studies will utilize recently developed rodent models to examine the following Specific Aims: (1) Characterize the mechanism by which LTB4 activates primary sensory nerves and induces pancreatitis;(2) Determine the role of TRPV1 in experimental ethanol-induced pancreatitis;and (3) Determine the relationship between tumor necrosis factor 1 (TNF1) and TRPV1 in experimental pancreatitis. These results should help both elucidate the importance of primary sensory innervation in the pathogenesis of pancreatitis and provide possible new strategies for the treatment of pancreatitis. PUBLIC HEALTH RELEVANCE: Pancreatitis is an inflammatory disease of the pancreas that causes intense pain and, in severe cases, death. Although some predisposing factors (such as gallstones and alcohol) are known, the exact mechanisms leading to pancreatitis are not well understood. Pain-sensing nerves release transmitters that may actually cause inflammation and preliminary data indicate that these nerves play a role in pancreatitis. This proposal will characterize the neural mechanisms that contribute to pancreatitis and may lead to improved treatments of the disease.